tbuckley/cabot-search huggingface dataset:
Reducing pre-analytical sample QC failure rates for cancer molecular genetic assays with SLIMamp technology.
Authors: Lynn Fink, Paul Michael Waring, Binny Jaradi, Nathan Stone, Lisa Anderson, Paul Leo, Mhairi Marshall, Jonathan Ellis, Kenneth O'byrne
Journal: Journal of Clinical Oncology (2022)

e15034 Background: Identification of somatic variants in cancer by high-throughput sequencing has become common clinical practice largely because many of these variants may be predictive biomarkers for targeted therapies. However, there can be high sample QC failure rates for some assays (sometimes up to 40%), preventing the return of results that may affect patient treatment decisions. Pillar Biosciences has incorporated their patented SLIMamp technology into commercially available cancer NGS testing kits with the claim that these kits can successfully interrogate challenging formalin-fixed paraffin-embedded tissue (FFPET) samples with low tumor purity, poor DNA quality, and/or low input DNA, resulting in a high sample QC pass rate. The aim of this study was to substantiate that claim using Pillar’s amplicon-based oncoReveal Solid Tumor Panel. Methods: We acquired 48 tumor samples that had failed one or more pre-analytical QC sample parameters for whole exome sequencing (WES) from ATGC’s ISO15189 accredited diagnostic genomics laboratory. XING Genomic Services performed an exploratory data analysis using our pre-analytical QC assays to characterise the samples and then sequenced the samples in our ISO15189 accredited laboratory using the validated oncoReveal Solid Tumor Panel. Results: We were able to achieve high sequencing coverage (&gt;3000X) for all 48 samples and explored the determinants of sample “success”. We were able to generate clinical reports for 45 samples (94%), of which 38 (79%) contained clinically actionable or significant variants that would not have otherwise been identified. Ten samples had a higher number of total variant calls with over-representation of C&gt;T transitions representing stochastically-amplified, formalin-induced artefacts in samples with very low input template DNA. Of these, 7 cases had reportable variants and 3 were deemed unreportable. We demonstrated that DNA integrity is the major determinant of success even in samples with low input DNA or low tumor purity and were able to further refine pre-analytical and post-analytical QC metrics to better identify samples with poor quality DNA that can be sequenced reliably. Conclusions: In this study, we showed that the Pillar Biosciences oncoReveal Solid Tumor Panel, which uses SLIMam technology, was able to generate reliable, interpretable results for 94% of samples that failed pre-analytical QC for WES, substantiating Pillar’s claim.
Nivolumab (NIVO) + tacrolimus (TACRO) + prednisone (PRED) +/- ipilimumab (IPI) for kidney transplant recipients (KTR) with advanced cutaneous cancers.
Authors: Kara M. Schenk, Julie E. Stein, Sunandana Chandra, Diwakar Davar, Zeynep Eroglu, Nikhil I. Khushalani, Jason J. Luke, Patrick Alexander Ott, Jeffrey A. Sosman, Vikram Aggarwal, Megan Davis Schollenberger, William Howard Sharfman, Elad Sharon, Serena M. Bagnasco, Janis M. Taube, Suzanne Louise Topalian, Daniel C. Brennan, Evan J. Lipson
Journal: Journal of Clinical Oncology (2022)

9507 Background: Cancer is a leading cause of death among KTR, but these patients (pts) have been excluded from trials of immune checkpoint inhibitors due to immunosuppression and risk of allograft loss. We report findings from the first prospective clinical trial of NIVO + TACRO + PRED +/- IPI in KTR with selected advanced cutaneous cancers. Methods: The primary composite endpoint was lack of tumor progression per RECIST v1.1 without allograft loss at 16 weeks (W) on NIVO. Adult KTR with advanced melanoma, basal, cutaneous squamous, or Merkel cell carcinoma (MEL, BCC, CSCC, MCC), for whom non-immune therapies were insufficient were eligible. Immunosuppression was standardized to low-dose TACRO (goal trough 2-5 ng/mL) + PRED 5mg daily; pts then received NIVO 480mg IV q4W. Pts with progressive disease (PD) could receive NIVO 3mg/kg + IPI 1mg/kg IV q3W x 4 followed by NIVO 480mg IV q4W. Donor-derived cell-free DNA (dd-cfDNA) levels were measured q2W as a potential predictor of allograft rejection. Results: From 11/2019 - 4/2021, of 12 pts enrolled, 8 pts with CSCC, MCC or MEL were evaluable for response (Table). All pts experienced PD on NIVO; treatment-related allograft loss (TRAL) occurred in 1 pt. 6 pts then received IPI + NIVO. Responses: 2 (33%) with marked tumor regression at 6W and eventual complete response (CR; 1 with TRAL), and 4 (67%) with PD (1 with TRAL). 7/8 pre-NIVO tumor biopsies contained a paucity of infiltrating immune cells. Only 2/5 on-NIVO biopsies demonstrated moderate immune infiltrates; both of these pts later developed a CR to IPI + NIVO. Rejecting allografts contained dense immune responses (plasma cells, CD4+ &amp; CD8+ lymphocytes, PD-1+ lymphocytes, macrophages, PD-L1+ glomerular endothelium, and focal PD-1 &amp; PD-L1 positivity in renal tubules). In 2/3 pts with TRAL, elevations in dd-cfDNA levels occurred 10 and 15 days earlier than increases in weekly serum creatinine levels. TRAL #3 occurred after discontinuation of study therapy (including TACRO) and dd-cfDNA monitoring. Conclusions: In KTR receiving low-dose TACRO + PRED, NIVO augments tumor immune cell infiltration in some pts but is insufficient to mediate tumor regression. Adding IPI can enhance anti-tumor immunity and mediate tumor regression. TACRO + PRED was insufficient to prevent allograft rejection after PD-1 +/- CTLA-4 blockade in 2/8 pts. In pts with TRAL, increased dd-cfDNA levels preceded increased serum creatinine. Based on these findings, we are modifying the trial therapy regimen to augment anti-tumor immunity and preserve allograft function. Clinical trial information: NCT03816332. [Table: see text]
Evaluation of circulating tumor cells in stage III colorectal cancer patients under three or six months of adjuvant therapy.
Authors: Ippokratis Messaritakis, Asimina Koulouridi, Maria Sfakianaki, Konstantinos Vogiatzoglou, Nikolaos Gouvas, Ioannis Tsiaousis, Elias Athanasakis, Evangelos Xynos, Ioannis Sougklakos, Ioannis Boukovinas
Journal: Journal of Clinical Oncology (2022)

e15601 Background: The duration of adjuvant oxaliplatin-combination treatment in stage III colorectal cancer (CRC) patients is still debatable. Circulating Tumor Cells (CTCs) have been proposed as a potential markers for detection of micrometastatic disease. The aim was to compare the elimination rate of CTCs in patients treated with three- and six-months treatment with FOLFOX or CAPOX, in stage III CRC patients. Methods: Peripheral blood samples were collected from 132 patients at baseline, after three (for all patients) and after six months (for those under six months treatment). Surgical specimens were collected from all patients for the evaluation of their genetic profiling using Sanger sequencing (Ras/Raf) and fragment analysis (microsatellite instability status). The detection and number of circulating tumor cells (CTCs) were evaluated using double immunofluorescence and a real time-polymerase chain reaction assay, at all three time points. Results: Median age of the patients was 62 years, 59.8% were males, 92.7% had a colon/sigmoid tumor location, 24.4% had tumor on the right colon and 99.2% had a good performance status (PS). Of all patients, 44.3% and 55.7% were treated with FOLFOX and CAPOX, respectively; patients received treatment for three and six months, were equally distributed. KRAS, NRAS and BRAFmutations were detected in 41.5%, 2.1% and 12.8%, respectively; whereas MSI-High status was detected in 9.8% of the patients. CTCs were detected in 43.2%, 42.4% and 54.2% of the patients, at baseline, after three and six months of treatment, respectively. Both positivity rate ( p&lt; 0.001) and absolute number of CTCs ( p= 0.022) were decreased between baseline and three months of treatment. Moreover, a significant increase was observed both on the positivity rate ( p= 0.053) and absolute number of CTCs ( p&lt; 0.001) between three and six months of treatment. Following Cox regression analysis, BRAF status and the detection of CTCs are significantly correlated with decreased time to progression. Conclusions: To conclude, the current study indicates that 3 months of adjuvant treatment is at least as efficacious as 6 months in eliminating CTCs. However, the increase of both the rate and number of positive CTCs after three months of treatment might highlight the emergence of resistant cancer cell clones.
Clinicopathological analysis of 285 cases of elderly patients with epithelial ovarian cancer.
Authors: Yuanqiong Duan, Mengpei Zhang, Rutie Yin, Jinbiao Han
Journal: Journal of Clinical Oncology (2022)

e17539 Background: Elderly patients with epithelial ovarian cancer often cannot receive standard treatment, and their survival time decreases with age, seriously threatening their lives. Elderly patients with epithelial ovarian cancer tend to have many complications and poor tolerance to surgery and chemotherapy, resulting in poor overall prognosis. Methods: The clinicopathological data of EOC patients aged ≥ 60 years old who were diagnosed and treated in our hospital from January 2013 to January 2018, with completed clinical and pathological data were collected for analysis and followed up through outpatient review, telephone, WeChat, QQ group, etc. to analyze the diagnosis and treatment plan and main prognostic factors. The deadline for follow-up was March 1, 2020. Results: Comparison of recurrence and the overall survival in different groups, the results respectively showed that the difference had statistically significant (χ2 = 255.027, p &lt; 0.001) 、(χ2 = 314.443, p &lt; 0.001). Analysis of the factors affecting the recurrence and death of patients showed that the results of single factor analysis showed age, BMI, Combined with cardiovascular and cerebrovascular diseases, pre-treatment CA125 value, thrombus score, FIGO staging, pathological type, residual lesion size are the influencing factors of recurrence. Further multivariate analysis showed that combined cardiovascular and cerebrovascular diseases, pre-treatment CA125 value, FIGO stage, residual lesion size is an independent factor affecting relapse. The median survival time of relapse-free in the neoadjuvant chemotherapy group was 39.00 (30.67̃44.95) months; the median survival time of relapse-free in the directing surgery group was 36.00 (29.47̃42.53) months, statistical comparison showed no significant difference (χ2 = 2.426, p = 0.119). The total median survival time of the neoadjuvant chemotherapy group was 49.57 months; for the directing surgery group, the total median survival time was 47.07 months, and the statistical comparison showed no significant difference (χ2 = 0.166, p = 0.684). Conclusions: For the epithelial ovarian cancer in elderly patients the results showed that the standard treatment group was better than the non-standard treatment group, chemotherapy-only group, surgery-only group, and untreated group. Comparing with primary tumor debulking surgery (PDS),neoadjuvant chemotherapy-Interval debulking surgery (NACT-IDS) group could improve the intraoperative situation，reduce the amount of intraoperative bleeding, shorten the operation time, reduce the wound healing rate and the incidence of surgical complications, but it had no effect on the tumor removal rate, PFS and OS.
Uncommon EGFR mutations on osimertinib, real-life data (UNICORN study): Updated results, brain efficacy, and resistance mechanisms.
Authors: Jair Bar, Nir Peled, Shiruyeh Schokrpur, Elizabeth Dudnik, Mira Wollner, Nicolas Girard, Frank Aboubakar Nana, Sofie Derijcke, Waleed Kian, Sandip P. Patel, Hadas Yocheved Gantz Sorotsky, Alona Zer, Mor Moskovitz, Giulio Metro, Yakir Rottenberg, Antonio Calles, Maximilian Hochmair, Kristof Cuppens, Lynn Decoster, Alfredo Addeo
Journal: Journal of Clinical Oncology (2022)

9109 Background: About 10% of EGFR mutations (EGFRm) are ‘uncommon mutations’ (ucEGFRm). osimertinib is a 3 rd generation EGFRi, active against common EGFRm. We aimed to collect real-world data about systemic and brain response and resistance mechanisms to osimertinib for ucEGFRm patients. Methods: This is a multi-center, retrospective study of ucEGFRm mNSCLC treated with osimertinib as first EGFRi. RECIST and RANO-BM response was evaluated by investigators. Progression free survival (PFS), overall survival (OS) and duration of response (DOR) were calculated from initiation of osimertinib. Mutations found at resistance were collected. Results: 62 patients (pts) were identified in 22 centers from 9 countries. Median age was 64 (35-91) years, 74% females, 84% Caucasian, never/former/current smokers were 48%/39%/11% respectively, ECOG PS was 0-1/2/3-4 in 84%/10%/5%. Histology was adenocarcinoma in 97%. The largest subgroups were G719X, de novo T790M and L861Q (Table). Compound EGFR mutations were found in 27 pts (44%), TP53 mutations in 21 pts (34%). In 17 cases (27%), compound mutations included the common L858R/deletion19 and/or de novo T790M. Most frequent metastatic sites were lung/bone/brain in 45%/44%/39%. Most frequent toxicities were gastrointestinal (32 pts, 52%) and skin (24 pts, 39%); 8 pts had grade 3-4 AEs. No grade 5 AE occurred. 3 pts had AEs leading to discontinuation. RECIST response (RR) was available for 53 pts, CR - 4 (8%), PR - 27 (51%), SD - 17 (32%), and PD - 5 (9%). Median DOR (mDOR) was 17.4 months (95% CI 9.1-NA). mPFS was 9.5 months (95% CI 8.5–17.4). mOS was 24.5 months (95% CI 17.4-35.1). See Table for efficacy in the major subgroups. 24 pts (39%) had brain metastasis at presentation, for 12 pts a brain response by RANO-BM was available with 25%/25%/33%/17% CR/PR/SD/PD. For 14 pts, rebiopsy mutation analysis at progression on osimertinib was available: 3 pts with an additional EGFR mutation (C797S,D585Y, E709K), 3 pts with a new TP53 mutation, 1 with c-Met amplification and 1 pt with transformation to neuroendocrine carcinoma. Conclusions: Osimertinib demonstrated activity in ucEGFRm with 91% disease control rate and encouraging PFS and DOR. Brain response was seen in 50% of cases. Several resistance mechanisms were identified. This report comprises, to the best of our knowledge, the largest dataset of osimertinib as the first EGFRi for ucEGFRm presented so far. [Table: see text]
LAG3-PD1 or CTLA4-PD1 inhibition in advanced melanoma: Indirect cross comparisons of the CheckMate-067 and relativity-047 trials.
Authors: Run-Cong Nie, Yun Wang, Shu-Qiang Yuan, Yingbo Chen, Zhiwei Zhou
Journal: Journal of Clinical Oncology (2022)

e21511 Background: There remain unmet needs to identify novel immune checkpoint inhibitors to improve the benefit-risk profile of immunotherapy for advanced melanoma. The comparison between LAG3-PD1 inhibition and CTLA4-PD1 inhibition was lacked. To compare the inhibition of lymphocyte-activation gene 3 (LAG3) plus programmed cell death 1 (PD-1) versus the inhibition of cytotoxic T-lymphocyte antigen 4 (CTLA-4) plus PD-1 in patients with previously untreated advanced melanoma. Methods: The individual participant data (IPD) data were extracted from the KM plots using a graphical reconstructive algorithm through eligible. Log-rank, Cox proportional hazard model, Bayesian hierarchical model with time-varying hazard ratio (HR) effect, and restricted mean survival time (RMST) were performed to estimate survival benefits. The primary endpoint was progression-free survival. Results: The CheckMate-067 (N = 630) and RELATIVITY-047 (N = 714) trials were included for analysis. The graphical reconstructive algorithm showed that IPD had similar HRs and log-rank values as the original plots. The HR of nivolumab-relatlimab (LAG3 inhibitor) versus nivolumab-ipilimumab (CTLA4 inhibitor) was 1.19 (95% confidence interval [CI] 0.96 to1.48). The 24-months RMST of nivolumab-relatlimab versus nivolumab alone was 2.35 (95% CI 0.77 to 3.94) months, compared with 1.87 (95% CI 0.25-3.49) months for nivolumab-ipilimumab versus nivolumab. The Bayesian hierarchical model showed that patients treated with nivolumab-relatlimab had earlier PFS benefits than those with nivolumab-ipilimumab. Grade 3 or 4 treatment-related adverse events occurred in 18.9% of patients using nivolumab-relatlimab and 55.0% of patients using nivolumab-ipilimumab. Conclusions: These findings suggest that the PFS of LAG3-PD1 and CTLA4-PD1 inhibition were similar and that LAG3-PD1 inhibition tended to exhibit earlier survival benefit and lesser TRAEs.
Geographic disparities in breast cancer mortality and place of death in the United States from 2003 to 2019.
Authors: Kelli Clemons, Amanda L. Blackford, Arjun Gupta, Parul Agarwal, Ross C. Donehower, Kristen Marrone, Syed Hussaini
Journal: Journal of Clinical Oncology (2022)

12034 Background: Breast cancer is the 2nd leading cause of cancer-related death in women with existing barriers in preventive services, access to treatment, and end-of-life care. There are unique sociopolitical challenges to rural healthcare with gaps in national health funding and hospice infrastructure. We investigated rural-urban disparities in age-adjusted mortality rates (AAMRs) and place of death in individuals dying from breast cancer. Methods: CDC WONDER database was utilized to analyze deaths from breast cancer from 2003 to 2019 using population classification per 2013 US Census: large metropolitan (≥1 million), small- or medium-sized metropolitan (50,000-999,999), and rural areas (&lt; 50,000). We extracted AAMRs by geographic area, age, and race/ethnicity. We estimated annual percentage changes (APC) in AAMR using robust linear regression models of the log-scale AAMR, including population size as weights, and assessed differential changes over time by geographic area with interaction tests. We estimated the percent of all deaths occurring in medical, hospice, and nursing facilities, and home. Odds ratios (OR) for the association between each place of death and individual-level characteristics were calculated using logistic regression, adjusting for year of death. Differential changes in place of death over time by geographic region were assessed with interaction tests. Results: From 2003 to 2019, there were 676,532 breast cancer-related deaths (52.9% large metro, medium/small metro 30.3%, rural 16.8%). Total AAMR declined from 39.8 to 30.9 during this period with rural areas noting least improvement (APC -1.24, 95% CI [-1.39, -1.09], p &lt; 0.001 for time trend) compared to large metropolitan (APC -1.74, 95% CI [-1.63, -1.46]). Non-Hispanic Black women had higher AAMRs among all racial/ethnic groups. Across all years, women in large metropolitan (OR 2.02, 95% CI [1.96, 2.07]) and medium/small metropolitan (OR 2.19, 95% CI [2.12, 2.25]) had higher odds of dying in a hospice facility compared to rural areas. Rural women died least often in a hospice facility (9.7% vs 14.5% large metropolitan vs 16.9% medium/small metropolitan in 2019), more often in a nursing facility (19.2% vs 12% large metropolitan vs 13.9% medium/small metropolitan) and slightly more often at home (44.6% vs 41.7% large metropolitan vs 43.4% medium/small metropolitan). Women in large metropolitan areas were most likely to die in a medical facility. Conclusions: Rural women with breast cancer experienced greater mortality and least annual improvement, with notable disparities in place of death. Our findings support interventions to improve access across cancer care continuum and congressional policy to urgently re-invest in cancer care access in rural areas.
Cost-utility of apixaban and rivaroxaban in the thromboprophylaxis of cancer patients treated with chemotherapy in Spain.
Authors: Laura Ortega, Andrés J. Muñoz Martín, Carlos Rubio-Terres, Dario Rubio-Rodriguez, Jose Manuel Soria
Journal: Journal of Clinical Oncology (2022)

e24102 Background: Apixaban and rivaroxaban are two direct-acting oral anticoagulants (DOACs) recommended for thromboprophylaxis in cancer patients treated with chemotherapy. The objective was to assess the cost-utility of thromboprophylaxis with apixaban and rivaroxaban vs no thromboprophylaxis in ambulatory cancer patients starting chemotherapy with an intermediate-to-high risk of venous thromboembolism (VTE), Khorana score ≥ 2 points. Methods: A cost-utility analysis was performed from the perspective of Spain´s National Health System (NHS) using an analytical decision model in the short term (180 days) and a Markov model in the long term (5 years). Transition probabilities were obtained from randomized, double-blind, placebo-controlled clinical trials of apixaban and rivaroxaban in adult ambulatory patients with cancer at risk for VTE, treated with chemotherapy (AVERT and CASSINI trials). The costs (€ 2021) were taken from Spanish sources. The utilities of the model were obtained through the EQ-5D questionnaire. Deterministic (base case) and probabilistic (second-order Monte Carlo simulation) analyses were conducted. Results: In the base case, apixaban was dominant (with a gain of 0.005 QALY, quality-adjusted life years, and a saving of €59.49 per patient) compared to no prophylaxis. Rivaroxaban would be cost-effective (with a gain of 0.006 QALY and an additional expense of €116.23 per patient) with a cost per QALY gained of €18,747 compared to no prophylaxis. For an willingness to pay of €25,000 per QALY gained, the probability that apixaban or rivaroxaban will be cost-effective would be 62.6% and 51.9%, respectively. Conclusions: VTE thromboprophylaxis with apixaban generates savings and with rivaroxaban it generates an additional cost vs. no prophylaxis. With both DOACs, a modest QALY gain would be obtained. The probability that prophylaxis with apixaban would be cost-effective is 10.7% higher than with rivaroxaban.